Barbituric acids and salts thereof



United States Patent BARBITURIC ACIDS AND SALTS THEREOF Fernanda Misani Fiordalisi, East Orange, N. 1., assignor to Air Reduction Company, Incorporated, New York, N. Y., a corporation of New York No Drawing. Application January 25, 1955, Serial No. 484,070

6 Claims. (Cl. 260-257) This invention relates to 5,5-disubstituted barbituric acids, and more particularly to certain S-substituted-S- (l',l-dialkyl-2-propynyl)-barbituric acids and salts thereof, their mode of preparation, and their use as hypnotics, sedatives and anesthetics.

The novel barbituric acids of this invention may he represented by the formula wherein R is an alkyl or alkenyl radical, which preferably contains from i to 3 carbon atoms, R1 and R2 are alkyl radicals and are preferably methyl or ethyl. Included within the scope of this invention are the pharmaceutically useful salts of the barbituric acids represented by the above formula. Suitabie salts include the alkali metals, e. g. sodium and potassium, the alkaline-earth metals, e. g. calcium, and substituted ammonium radicals. Representative of the compounds included within the scope of this generic formula are:

The novel compounds of this invention are physiologically active and have utility as sedatives, hypnotics and anesthetics. It has been further found that the compounds of the above formula wherein R is ethyl and R1 and R2 are either methyl or ethyl, are characterized by unexpectedly rapid hypnotic action coupled with a hypnotic chest of unusually long duration. Thus, for example, S ethyl-5-(l'-ethyl-l'-methyl-2-propynyl)-barbituric acid and 5-ethyl-5-(l',1'-dimethyl-2-propynyl)-barbituric acid, in view of their ability to rapidly induce hypnosis or sleep which will last for a relatively long time, possess properties long sought after for an hypnotic and may be of value when used as an anesthetic intravenously or when employed in conjunction with the well known inhalant anesthetics.

The barbituric acids and salts thereof can be incorporated in conventional pharmaceutical extending media, liquid or solid, for the preparation of therapeutically useful compositions. Such dosage forms may vary from sterile pyrogen-free aqueous solutions to solid tablets containing one or more inert compatible diluents or fillers. The compounds of this invention may be administered in 2,776,289 Patented Jan. 1, 1957 suitable hypnotic, anesthetic or sedative doses (average adult hypnotic dose ranges from 32-500 mg., depending upon me weight of the subject and the effect desired) by the conventional routes for the administration of barbiturates including oral, rectal, subcutaneous and intramuscular and intravenous. The compounds of this invention may he used in combination with analgesics, such as pyramidon, antipyrine, acetyl salicylic acid, codeine, and the like.

The S-substituted 5 (l,l'-dialkyl-2'-propynyl)-barbituric acids as represented by the formula given above may be prepared by alkynylation of the corresponding S-monosubstituted barbituric acid, or salt thereof, with a 1,1- dialkyl-Z-propynyl halide according to the equation wherein R is an alltyl or alltenyl radical, each of R1 and R2 is an alkyl radical, M may be hydrogen, an alkalimetal, or an alkaline-earth metal, and X is a halogen.

In preparing the barbituric acids of this invention in accordance with the procedure of this invention, the appropriate S-mono-substituted barbituric acid is preferably first converted to its metal salt by reaction with an alkali metal or alkaline-earth metal oxide or hydroxide, and the pH of the resulting mixture adiusted to remove any excess alkalinity. The resulting metal S-mono-substituted barbiturate is alkynylated by reaction with the appropriate dialkyl propynyl halide in the presence of an inert solvent reaction medium. The reaction is advantageously also carried out in the presence of a catalyst, which preferably is cupric sulfate. The alkynylation reaction can be conducted over a wide range of temperatures which may vary from about 15 C. to about C.; optimum results are obtained in the range of 60 C. to 70 C. Throughout the reaction period it is desirable to agitate the reaction mixture by any convenient means.

Pharmaceutically useful salts of the barbituric acids of this invention may be prepared by the conventional methods. For example, a stoichiometric amount of the desired barbituric acid is interreacted with a base containing the selected metallic or metallic-like cation in a reaction media such as ethanol, followed by recovery of the desired salt reaction product. Suitable salts include the alkali metals, e. g. sodium and potassium, the alkaline-earth metals, e. g. calcium, and substituted ammonium radicals, e. g. ethanolamine, ethylenediamine, tetra-alkyl ammonium hydroxide, and the like. All of the above barbituric acids can be converted to their salts by neutralizing with the proper amount of salt-forming base.

The following examples will serve to more specifically illustrate this invention.

and sufiicient water to dissolve the product. The mixture was filtered, and the pH of the filtrate was adjusted to 7.5 by the addition of a few drops of dilute hydrochloric acid. To the filtrate there were added 5.2 g. (0.05 mole) of 3-chloro-3-methyl-butyne-1 (prepared as described by Hennion, J. Am. Chem. Soc. 72, 3542, (1950)) and 2 cc. of a 10% cupric sulfate solution. The mixture was gradually brought to refluxing temperature. After about .1: hour, the temperature was 80 C. and the pH was below 3. The mixture was refluxed for two hours, and the reac tion mixture was then cooled and filtered. The residue was washed with water, recrystallized twice from acetone.

-a.llyl-5-(1',l'-dimethyl-2-propynyl)-batbituric :arid thus prepared had a melting point of 210214 C., and is insoluble in aqueous sodium bicarbonate at room temperature.

Analysis.Calcd. for C12H14O3N2: C, 61.52: H. 5.97: N, 11.96. Found: C, 61.55; H, 6.24; N. 1255.

Pharmacological studies.5-allyl-5-( l. l -KiliTREIhYl'Z propynyl)-barbituric acid was converted to the watersoluble sodium salt by the addition of an equivalent amount of 0.1 N NaOH, and made up in a range of doses varying from 75 mg./kg. animal wgt. to .150 nag/kg. animal wgt. for intraperitoneal injection of white rats. Onset of hypnosis occurred in from 5 to 7 minutes and lasted for from 3 to more than 5 hours. Some convulsive action was noted with the onset of, and recovery from, the hypnotic eflect.

EXAMPLE 2 S-ethyl-S-(I'J '-dimethyl-2-propynyl) -barbz'turic acid S-ethyl barbituric acid (28 g.) was dissolved in a solution made up of 7 g. of NaOH in 632 cc. of water. The mixture was filtered and the pH of the filtrate was adjusted to 7. The filtrate was placed in a 3-necked flask equipped with a stirrer, condenser and thermometer. Ethanol, 72 ml., and 18.5 g. of 3 chloro-3-methylbutyne-l were added. Then, 24 ml. of a 2% solution of cupric sulfate was also added. The mixture was stirred and heated to a temperature ranging from 60-65 C. The reaction was continued for about 2 hours, a precipitate appeared, and the reaction mixture was acidic. The reaction mixture was cooled and filtered. The precipitate was recrystallized twice from ethanol solution.

5-ethyl-5-( 1 ',1'-dimethyl-2'-propynyl) -barbituric acid thus prepared (yield about 10.5 g.) had a melting point of about 265 C. and is insoluble in 10% NaHCOs solu tion.

Analysis.-Calcd. for C11H14N20s2 C, 59.45: H. 6.30. N, 12.61 Found: C, 60.0, 59.80; H, 6.42, 6.29; N. [2.07.

Pharmacological studies.5-ethyl-5-( l',1'-dimethyl-2- propynyl)-barbituric acid was dissolved by the addition of a stoichiometric amount of NaOH and prepared in aqueous solution so 1 cc. of solution was equal to 20 mg. of the sodium salt of 5-ethyl-5-(l',1'-dimethyl-2'-pro pynyl)-barbituric acid. Rats were given doses ranging from 40 mg./kg. wgt. of animal to 120 rugs kg. wgt. of animal intraperitoneally. At the lower levels mild sedation but no narcosis occurred. At the higher dosage level narcosis occurred in 8 minutes. breathing was slow to regular, there were no convulsive movements, sleep was quiet and restful. The animals awoke after 4 hours. This compares with sodium phenobarbital which at similar dosage levels requires 30 minutes for the onset of narcosis, and the length of sleep as a rule is two hours. 5-ethyl-5-(1,1'-dimethy1-2'-propynyl)-barbituric acid is a rapidly acting barbiturate whose activity is of a long duration.

EXAMPLE 3 (a) S-ethyl-S-(I'-ethyl-I'-methyl-2'-propynyl)-barbituric acid g. of S-ethyl barbituric acid was dissolved in a solution made up of 4 g. of NaOH in 300 ml. of water. The resulting mixture was filtered, and the filtrate adjusted to a pH of 7 by the addition of HCl. The neutral filtrate was placed in s 328061; flask equipped with a stirrer, condenser and thermometer. Ethanol, 40 ml., and 11.6 g. of 3-chIor0-3-methyl-pentyne-1 (described by Campbell, I. Am. Chem. Soc. 60, 2882 (1938) and prepared as described by Hennion, J. Am. Chem. Soc. 72, 3542 (1950) for the lower homolog, 3-chloro-3-methyl-butyne-1) and 12 ml. of a 2% cupric sulfate solution were added. The mixture was heated to about 65" C. while stirring. The reaction was continued for about 2% hours. The mixture was cooled and filtered. The precipitate was washed with water, and recrystallized four times from an acetonewater solution; and once more from absolute ethanol.

S-ethyl 5 (1'-ethy1-1'-rnethyl-2'-propynyl)-barbituric acid had a melting point of about 222-225 C.

Analysis.-Calcd. for C12HisOaN2: C, 61.03; H, 6.82. Found: C, 61.10; H, 7.13.

(b) 5-ezhyl-5-( I -ethyl-1 -methyl-2 '-pr0pynyl) -barbituric acid g. of S-ethyl barbituric acid were dissolved in a solution of 12 g. of NaOH in 900 ml. of H20. The mixture was filtered and the pH of the filtrate adjusted to 7 with. 10% HCl. The filtrate was then placed in a 2 liter, three-necked flask equipped with a thermometer, stirrer and condenser. To the flask were added: 120 cc. of ethanol, 34.8 g. of 3-chloro-3-methyl-pentyne--1, and 366 cc. of a 2% cupric sulfate solution. The mixture was heated, while stirring, to a temperature of C., and the reaction was continued at this temperature for 2 /2 hours. The reaction mixture was cooled and filtered. The precipitate was recrystallized from an ethanol-acetone mixture, then recrystallized from ethanol, and then washed with an ethanol-water (ratio by volume 1:3) mixture. The crystals were then ground in a mortar to a line powder, and stirred with 200 cc. of a 5% NaHCOs solution. The mixture was filtered, and the precipitate was washed with water and recrystallized twice from ethanol.

5 ethyl-5-(1-ethyl-1'-methyl-2-propynyl)-barbituric acid prepared in accordance with this example had a melting point of 225-226 C.

Analysis.-Calcd. for C12H1603N2Z C, 61.03; H, 6.82; N, 11.80. Found: C, 61.00; H, 6.88; N, 12.02.

Pharmacological studies.5-ethyl-5-( l'-ethyl-l -methyl- 2'-propynyl)-barbituric acid was dissolved in an equivalent amount of sodium hydroxide upon gentle heating. Several rats were injected intraperitoneally with solutions in dosages ranging from 40 mg./kg. wgt. of animal to 120 mg./kg. wgt. of animal. Narcosis was induced in from 8 to 10 minutes at the lower dosage level and in from 4 to 5 minutes at the higher dosage level. Sleep lasted from 53 to 63 minutes at the lower dosage level and more than minutes at the higher dosage level. Respiration and heartbeat were not adversely affected. The compound was administered orally to two rats in a dosage of 180 mg./kg. wgt. of rat; sleep lasted about four hours. The compound in a dosage of 60 mgJkg. wgt. of animal, was injected intravenously in a dog; excellent anaesthesia was produced which lasted for the duration of an operation performed on it, i. e. for 2 hours. The compound is prompt acting and long acting, and compares favorably with the well-known barbiturates Nembutal and Phenobarbital. The duration of sleep pro duced by the compound of this example lasted 120 minutes whereas that produced by similar doses of Nembutal lasted only 30 minutes. The onset of sleep took about 20 minutes with equivalent dosages of phenobarbital, whereas sleep was induced in about 10 minutes with the compound of this example.

mixture was heated at reflux for a short time. A fine white precipitate appeared and cc. of ethyl ether was added. The reaction mixture was filtered, and the precipitate was washed with ethyl ether.

Analysis.Calcd. for Cizl-lmNzOs-Na: C, 55.81; H, 5.81. Found: C, 54.37, 54.17; H, 5.40, 5.55.

Pharmacological studies.The compound, as prepared in Example 4 above, was made up in 1% solution in water. Rats were injected intraperitoneally at dosage levels of 60 mgJkg. wgt. of animal and 70 mg./kg. wgt. of animal. Sleep was induced in from to minutes which lasted from about 2 to 4 hours. The aqueous solution of the sodium salt appears stable, since solutions injected eleven days after preparation (dosage 70 mg./kg. wgt. of rat) induced slap in rats within 10 minutes which lasted the average of four hours.

EXAMPLE 5 5-methyl-5-(1'-ethyl-1'-methyl-2'-propynyl)- barbituric acid 43 g. of S-rnethyl barbituric acid were dissolved in cc. of l N sodium hydroxide and 120 cc. of water. A few drops of 6 N H2804 were added to adjust the pH to 8.5. To this mixture were added 5 g. of 3-chlor0-3- methyl-pentyne-l, cc. of ethanol, and 5 cc. of a 2% cupric sulfate solution. At this point it was necessary to again adjust the pH to 8.5, since it had fallen to about 1.5. The mixture, while stirring, was heated at 65 C. for 2 hours. The reaction mixture was cooled, filtered to remove inorganic insoluble salts. The filtrate was acidified by the addition of HCl to bring the pl-I to about 3, and the resultant solution concentrated to dryness. The precipitate thus obtained was further purified by taking it up in boiling methanol and removing the insoluble materials by filtration. The methanol filtrate was concentrated to near dryness, and the resulting precipitate was recrystallized from aqueous ethanol. The product was further purified by suspending it in 200 cc. of a 5% RaHCOa solution. The suspension was filtered, and the precipitate was washed with water and recrystallized twice from ethanol to obtain the desired product as fine slightly colored needle crystals.

5-methy1-5-(l'-ethyll-methy1-2-propynyl) barbituric acid had a melting point of 219-220 C. and was insoluble in sodium bicarbonate.

Analysis.-Calcd. for CnHuOsNa: C, 59.45; H, 6.30. Found: C, 59.05; H, 6.30.

Pharmacological studies-5 methyl 5 (l'-etl1yl-lmethyl-2'-propynyl)-barbituric acid was converted into its water-soluble sodium salt by the addition of an equivalent amount of 0.1 N NaOl-I. A 1% aqueous solution of this salt was prepared. The solution was injected intraperitoneally at a dosage range of from mg./kg. wgt. of rat-200 rug/kg. wgt. of rat into a series of white male rats. At the upper dosage levels slight sedation occurred. The compound may be useful as a mild sedative.

It will be understood that the foregoing examples are not limitative but merely illustrative of the present invention. Various modifications may be made with respect to procedures and/or compositions without departing from the scope of this invention. The invention is not to be limited except as defined in the appended claims.

What is claimed is:

1. Hypnotic and sedative compounds selected from the group consisting of compounds represented by the formula H-N( i R 1 11-N-d ozon ll R2 wherein each of R1 and R2 is a radical selected from the group consisting of methyl and ethyl, and the pharmaceutically useful salts thereof.

2. S-ethyl-S-l,l'-dimethyl-2'-propynyl) barbituric acid. 3. Sodium 5-ethyl-5-( 1',l-dimethyl-2'-propynyl)-barbiturate.

4. 5-ethyl-5-( l'-ethy1- l '-rnethyl-2'-propynyl) -barbituric acid.

5. Sodium 5-ethyl-5-(l'-ethyl-l'-methyl-2'-propynyl)- barbiturate.

6. 5-methyl-( 1'-ethyl-l'methy1-2'-propynyl)-barbituric acid.

References Cited in the file of this patent UNITED STATES PATENTS 1,682,062 Bockmuhl et a1 Aug. 28, 1928 

1. HYPNOTIC AND SEDATIE COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS REPRESENTED BY THE FORMULAR 